Can Cardizem (diltiazem) be added to a patient already taking isosorbide mononitrate and nitroglycerin (NTG) ointment for angina?

Adding Cardizem (Diltiazem) to Nitrate Therapy for Angina

Yes, diltiazem can be safely added to nitroglycerin ointment and isosorbide mononitrate for angina management, as this combination is explicitly supported by guidelines and commonly used in clinical practice. 1, 2

Guideline Support for Combination Therapy

The combination of calcium channel blockers (including diltiazem) with nitrates is a well-established approach for angina management:

• The 2012 ACC/AHA guidelines explicitly state that calcium channel blockers in combination with beta blockers should be prescribed for relief of symptoms when initial treatment with beta blockers is unsuccessful. 1 This same principle applies when combining with nitrates.

• The FDA-approved diltiazem label specifically states: "Prophylactic Nitrate Therapy: Diltiazem hydrochloride may be safely coadministered with short- and long-acting nitrates." 2 This directly addresses your question about combining diltiazem with NTG ointment and isosorbide mononitrate.

• The 2018 Nature Reviews Cardiology expert consensus document on personalized angina treatment confirms that double and sometimes triple therapy with different classes of antianginal drugs is often needed. 1

Clinical Rationale for This Combination

The combination works through complementary mechanisms:

• Diltiazem provides coronary and peripheral vasodilation with negative chronotropic effects (heart rate reduction), while nitrates primarily cause venodilation and coronary vasodilation. 3 These mechanisms are additive rather than redundant.

• For patients with high heart rate (>70 bpm), diltiazem is particularly valuable as a heart-rate-lowering agent, which nitrates cannot provide. 1

• In vasospastic angina, diltiazem is particularly effective when used alone or in combination with nitrates. 3

Critical Safety Considerations

Before adding diltiazem, you must assess for specific contraindications:

Absolute Contraindications to Adding Diltiazem:

• Severe left ventricular dysfunction or pulmonary edema 1, 3
• High-degree atrioventricular block 1
• Concurrent beta-blocker use (relative contraindication due to risk of high-degree AV block) 1, 3
• Concurrent ivabradine use (absolutely contraindicated) 1, 3

Blood Pressure Monitoring:

• Both calcium channel blockers and nitrates significantly decrease blood pressure. 1 A reasonable threshold for caution is systolic BP <130 mmHg or diastolic BP <80 mmHg in patients with coronary artery disease. 1

• Monitor for hypotension, which can paradoxically worsen angina by impairing coronary perfusion. 1

Heart Failure Considerations:

• The 2012 ESC Heart Failure guidelines explicitly state: "Diltiazem or verapamil are not recommended because of their negative inotropic action and risk of worsening HF." 1 This is a Class III recommendation (harmful).

• If the patient has any evidence of left ventricular systolic dysfunction (LVEF ≤40%), diltiazem should be avoided entirely. 1

Practical Implementation

Dosing Strategy:

• Start diltiazem at 30 mg four times daily, before meals and at bedtime, then increase gradually at 1-2 day intervals. 2
• The average optimum dosage range is 180-360 mg/day. 2
• Continue the existing nitrate regimen (isosorbide mononitrate and NTG ointment) unchanged initially. 2

Monitoring Parameters:

• Check blood pressure and heart rate before each dose escalation. 1
• Monitor for symptoms of hypotension (dizziness, lightheadedness). 3
• Assess for bradycardia or AV block (PR interval prolongation). 3, 4
• Watch for peripheral edema, headache, and flushing. 3

Evidence from Clinical Trials

Research supports the safety and efficacy of this combination:

• A 1989 study directly evaluated diltiazem combined with isosorbide-5-mononitrate in 25 patients with stable angina. 4 The combination was well-tolerated, though headache was common (occurring in 11 patients on combination therapy). 4

• The combination did not show additional exercise capacity benefit over diltiazem alone in this study, but this may have been due to inadequate nitrate dosing or tolerance development. 4

• Multiple studies confirm diltiazem's efficacy is similar to nitrates in exertional angina, with less than 5% of patients experiencing adverse effects. 5, 6

Common Pitfalls to Avoid

• Do not add diltiazem if the patient is already on a beta-blocker without careful consideration and close monitoring, as this combination significantly increases risk of high-degree AV block. 1

• Ensure the patient is not taking sildenafil or other phosphodiesterase inhibitors, as the combination with nitrates is contraindicated. 1

• Be aware that headache is very common when combining calcium channel blockers with nitrates 4 - counsel the patient that this often improves with continued use.

• Monitor for nitrate tolerance, which can develop with continuous nitrate exposure. 1 Consider a nitrate-free interval if using long-acting nitrates.